This is a 371 of PCT/EP00/63485 filed Apr. 18, 2000.
The present invention relates to the use of N-acetylcysteine for intravenous administration in dialysed patients to prevent oxidative stress, which is responsible for the onset of numerous diseases.
The number of patients suffering from renal disease is constantly growing all over the world. The number of these patients starting with dialysis is growing too at a rate of 7-9% each year and it has been calculated that there will be more than 350,000 dialysed patients in the USA in 2010.
The hemodialysis procedure is usually carried out three times a week so totalling 156 times a year.
Recent studies have shown that hemodialysis is associated with oxidative stress (see for example the book xe2x80x9cHaemodialysis and Oxidant Stressxe2x80x9d Editors: Norbert Lameire, Gent; Ciro Tetta, Mirandola; Claudio Ronco, Vicenzaxe2x80x94Reprint of xe2x80x9cBlood Purificationxe2x80x9d, vol. 17, No. 2-3, 1999).
Reactive oxygen species are generated as a consequence of cellular metabolism but the dialysis procedure causes a spontaneous and increased production of oxygen radicals. This phenomenon gives raise to several side effects such as lipid peroxidation, protein thiol group oxidation, DNA damage and release of proinflammatory molecules (for example cytokines) due to the oxidative stimulus.
From that, a number of noxious effects exerts such as anaemia, increased susceptibility to infections, accelerated atherosclerosis which has as a consequence the onset of cardiovascular diseases, the main cause of mortality in chronic dialysed patients (responsible for about half of all deaths). In particular, a high prevalence of vascular damages and of congestive heart failure has been observed.
N-acetylcysteine (hereinafter referred to as NAC) is a known drug (The Merck Index, XII ed., page 16, no. 89) used from decades in therapy, mainly as mucolytic.
Moreover, the detoxifying properties of NAC are widely known suggesting its use in the treatment of several pathologies, for example in the liver protection after intoxication from drugs such as paracetamol.
As for the treatment of patients undergoing dialysis, the oral administration of NAC has been recently described in the literature [Atherosclerosis 120 (1996) 241-244] to be without efficacy.
We have now surprisingly found that the preventive intravenous administration of NAC is able to decrease the effect of the oxidative stress in dialysed patients.
Therefore, object of the present invention is the use of NAC or pharmaceutically acceptable salts thereof for the preparation of a medicament suitable for the intravenous administration to prevent oxidative stress in dialysed patients.
Pharmaceutically acceptable salts of NAC which can be used according to the present invention are inorganic salts, preferably sodium salts.
NAC is preferably used.
The use of NAC or of its salts according to the present invention is a preventive use.
Then, NAC or its salts will be administered in a dosage form pharmaceutically suitable for the intravenous use, generally an aqueous solution, before and during the dialysis session, which generally lasts 3-5 hours.
The dose of NAC or of its salts to be administered for hemodialysis in acute renal disease treatment is generally from 100 to 200 mg/kg, preferably about 160 mg/kg.
The dose of NAC or of its salts to be administered for hemodialysis in the chronic treatment is generally from 500 to 5000 mg, preferably from 1 to 2 g.